Rabies is a major global health issue that kills approximately 40,000 to 70,000 people per year and over 10 million people who receive post-exposure prophylaxis (PEP) after exposure to potentially infected animals. Cost and compliance issues have greatly hampered the effectiveness of current vaccines. To confound this issue, current vaccines are not effective at preventing disease from several newly identified rabies related viruses. In addition, live rabies virus (RV) was recently discovered in a lot of vaccine that was supposed to contain inactivated RV. Taken together, the development of novel pre- and post-exposure vaccines is necessary to combat this global health issue. Since pre-exposure vaccination is reserved only for those at-risk populations, such as laboratory workers and veterinarians, PEP is the world-wide standard for human rabies prevention. Current PEP is comprised of one dose of passive immunization [(rabies immune globulin (RIG)] along with five active immunizations with inactivated rabies vaccines. The experiments in this proposal are designed to test the hypothesis that a matrix (M) gene-deleted RV vaccine vector would make an excellent RV PEP that requires only one to two doses. Of note, since this vector lacks one of its five essential genes, it is replication-deficient and very safe. A hallmark of RV infection that makes PEP feasible is the relatively long period between the time of exposure at the peripheral site and the time when RV infects the central nervous system. As such, a rapid humoral response is absolutely required for a successful PEP. Therefore, we will measure the kinetics of the induced humoral immune response in mice after only one or two doses of the M- deleted RV vaccine vector. The responses will be compared with mice inoculated with the current six-dose inactivated vaccine regimen. In summary, the development of a treatment that relies on only one to two doses of vaccine instead of six inoculations will greatly enhance the effectiveness of human RV prevention, resulting in potential life-saving and cost-reducing vaccines in both developed and developing countries. PUBLIC HEALTH RELEVANCE: The goal of this application is to develop safe and effective alternatives to the current human rabies post- exposure prophylaxis. The development of treatment that relies on only one to two doses of vaccine instead of six inoculations will greatly enhance the effectiveness of rabies virus prevention, save lives and reduced costs in developing and developed countries.